Thangaiah, Judith Jebastin

Background: Localized soft tissue sarcoma (STS) is primarily treated with surgical resection with or without radiotherapy (RT), while the role of chemotherapy (CT) as a radiosensitizer remains unclear. We report our single-institution experience with combined chemoradiotherapy (CCRT) in treating localized STS. Methods: We conducted a retrospective analysis of patients with localized STS treated at Mayo Clinic with mitomycin, cisplatin, and doxorubicin (MitoAP) concurrently with RT between 1/1/85 and 12/12/19. Results: We identified 179 patients (median age 58 years; median tumor size 9.5 cm), with 83.8% of tumors located in the extremities or trunk. Among them, 77.1% received perioperative CT in addition to CCRT, with 95% of those treated in the neoadjuvant setting. Median RT dose was 50 Gray. The 5-year disease-specific survival (DSS) was 77.9% (95% confidence interval, CI: 70.8–83.4%). The addition of perioperative CT to CCRT was associated with improved DSS compared with CCRT alone (p = 0.01, Hazard Ratio, HR: 0.48, 95% CI: 0.27–0.85). Median post-CCRT tumor viability was 30% and did not differ by CT use (p = 0.39), but varied significantly by histology (p < 0.001). Conclusions: Our institutional protocol utilizing two cycles of MitoAP with RT was well tolerated. DSS in our cohort was similar to historical data using perioperative RT alone, suggesting no clear benefit from CCRT. However, the majority of patients in our cohort were classified as high risk, which may have attenuated a potential survival benefit in the absence of appropriate comparative controls. Furthermore, additional perioperative CT to CCRT was associated with improved DSS and differential histology-specific responses in tumor viability, suggesting that a more aggressive neoadjuvant and perioperative approach may be beneficial in selected patients.

With the first series of PRRX1 -rearranged tumors published in 2019, the spectrum of these so-called fibroblastic tumors has been expanded. Since then, several smaller case series have been published; however, our understanding of them continues to be quite limited given their rarity. We herein studied 18 additional cases, the largest series to date. Eighteen tumors present in 9 male, 8 female, and 1 nonbinary patient with a median age of 35 years (range: 11 to 70 y) and involved the neck (5), the chest region (4), thigh (3), back (1), shoulder (1), forehead (1), lower leg (1), axilla (1), and the parapharyngeal region (1). Clinical follow-up (9/18 tumors; 50%; median: 10 mo; range: 4 to 40 mo) showed consistent indolent behavior without local recurrences or distant metastases. On morphology, these tumors were characterized by well-circumscription and distinctive peripheral crescent-shaped vessels. They were composed of uniform spindle and round cells growing in short fascicles within often densely hyalinized collagen lacking significant mitotic activity, necrosis, or cytologic atypia. Immunohistochemically, about half of the tested tumors expressed focal to rarely diffuse S100 with occasional co-expression of SOX10. Interestingly, almost half of the tested cases also showed complete loss of RB expression. All but 1 tumor harbored a PRRX1::NCOA1 fusion, while 1 case harbored a novel PRRX1::EP300 fusion. We herein provide additional data on these exceptionally uncommon tumors, expand their molecular spectrum, and compare them to their close morphologic mimics to aid in accurate diagnosis and avoid confusion with potentially more aggressive neoplasms.

Abstract Background We retrospectively assessed volumetric response of myxoid liposarcoma (MLPS) with preoperative radiotherapy (RT) and sought to identify disease and treatment characteristics associated with response. Patients and methods We identified all patients with a histologic diagnosis of MLPS who received preoperative RT from 2013 to 2021 at our institution. We used cone beam computed tomography (CBCT) to assess changes in tumor volume and greatest dimension during treatment. Tumors were contoured on CBCT images prior to treatment and at the end of each week of RT. Percentage change in tumor volume and greatest dimension were calculated based on pre-treatment and final week contours. Patients with tumors incompletely visualized on CBCT were excluded from volume analysis but included on greatest dimension analysis. Magnetic resonance imaging (MRI) was used to evaluate pre- and post-RT radiographic features. Surgical pathology was reviewed to record pathologic characteristics. Results Twenty patients met inclusion criteria. Most tumors (18/20) were low grade. The most frequent dose/fractionation scheme was 50 Gy in 25 fractions (16/20), with 3 patients receiving 36 Gy in 18 fractions. Median pre-RT volume and greatest dimension were 120 cc (interquartile range [IQR]: 56–399) and 11.2 cm (IQR: 8.4–14.1), respectively. Median percentage change in volume and greatest dimension were -37% (IQR: -57 to -29) and -10% (IQR: -20 to -7). All evaluable tumors decreased in volume during RT. Between pre- and post-RT MRI, most patients had a decrease in intratumoral (16/20) and peritumoral edema (11/20). Sixteen patients exhibited extensive pathologic response. There were no significant associations between radiographic and pathologic features and volumetric change. Local failure at 3 years was 9% (95% confidence interval: 1–59). Conclusions We report significant decreases in MLPS tumor size during preoperative RT. There may be a role for adaptive RT planning to reduce target volumes and minimize RT-associated morbidity.

Myoepithelial tumors are typically characterized by distinct molecular profiles that have been shown to correlate with their anatomical locations. EWSR1 or FUS rearrangements are common in cutaneous, soft tissue and bone tumors, whereas salivary gland myoepithelial tumors are frequently associated with PLAG1 and HMGA2 alterations. This apparent molecular divergence led some previous studies to doubt a common pathogenetic relationship between myoepithelial tumors of soft tissue and bone with their salivary gland counterparts. Herein, we present primary intraosseous myoepithelioma harboring HMGA2::WIF1 fusion. This fusion has been previously identified in a range of salivary gland myoepithelial tumors including myoepitheliomas, myoepithelial carcinomas arising from pleomorphic adenomas, and pleomorphic adenomas themselves. Primary myoepithelial tumors of the bone are exceedingly rare, and to our knowledge, HMGA2 rearrangements have not been previously reported in soft tissue or bone myoepithelial neoplasms. Through this report, we aim to enhance the existing literature on myoepithelial neoplasms, while highlighting the importance of recognizing primary bone myoepitheliomas and contributing to a broader understanding of the pathogenetic landscape of myoepithelial tumors across diverse tissue types.

SUMMARY Ewing sarcoma (EwS) is a group of bone and soft tissue cancers in children and young adults. Since EwS cells have pronounced sensitivity to radiation and chemotherapy-induced DNA damage, the role of the oncoprotein, EWS-FLI1, in DNA repair is likely. Here, we demonstrate that EWS-FLI1 causes a defect in microhomology-mediated end-joining (MMEJ) repair. EWSR1 is a splicing factor that promotes the faithful splicing of the POLQ pre-mRNA, required for the expression of POLΘ, a critical protein in the MMEJ pathway. Expression of EWS-FLI1, or loss of EWSR1, causes exon 25 skipping of the POLQ transcript, decreased POLΘ expression, impaired MMEJ, and cellular sensitivity to inhibitors of the Fanconi Anemia (FA), NHEJ, or HR pathways, through the mechanism of synthetic lethality. Knockdown of EWS-FLI1 expression restores POL0 mitotic foci and increases MMEJ activity. Inhibitors of the FA, NHEJ, or HR therefore may provide a targeted therapy for patients with EwS. Highlights - Ewing sarcoma tumors have a deficiency in POLθ expression and a corresponding loss of MMEJ activity - EWSR1 is a splicing factor that interacts with other splicing factors such as FUBP1 and KHSRP/FUBP2 to accurately splice the POLQ mRNA. - The EWS-FLI1 fusion oncoprotein, or loss of EWSR1, causes a splicing defect, leading to exon25 skipping of the POLQ pre-mRNA and loss of POLθ expression - The MMEJ deficiency of EwS cells results in cellular sensitivity to inhibitors of Fanconi Anemia, Homologous Recombination or Non-Homologous End-Joining - Exon 25 skipping of POLQ mRNA is a predictive biomarker for HR inhibitors in human cancers

Background: Myxoid liposarcoma predominantly affects young and middle-aged individuals, and little is known regarding treatment tolerability and outcomes in older patients. This study aims to better understand this older patient population. Methods: This single institution retrospective study included patients aged 70 years and older with localized (non-metastatic) myxoid liposarcoma. Results: Sixteen patients were included. The median age was 75 years, and 9 (56%) were female. Fourteen (88%) were extremity tumors and two (12%) were trunk. The median tumor size was 10.4 cm (range, 3.6 to 28 cm). Five (31%) tumors had a round cell component. All patients had surgery. Fourteen (88%) had perioperative radiation, and three (19%) had perioperative chemotherapy. One patient had postoperative infection, and one patient had neutropenic fever from preoperative chemotherapy. The median follow up from surgery was 6.3 years. Eight (50%) patients died from MLPS. The median relapse-free survival and overall survival were 34 months and 75 months, respectively. Conclusions: Most older patients with localized MLPS received perioperative radiation therapy with surgery, and few serious toxicities were reported. Even with treatment, half of the patients relapsed.

Abstract Background The authors previously developed an artificial intelligence (AI) to assist cytologists in the evaluation of digital whole‐slide images (WSIs) generated from bile duct brushing specimens. The aim of this trial was to assess the efficiency and accuracy of cytologists using a novel application with this AI tool. Methods Consecutive bile duct brushing WSIs from indeterminate strictures were obtained. A multidisciplinary panel reviewed all relevant information and provided a central interpretation for each WSI as being “positive,” “negative,” or “indeterminate.” The WSIs were then uploaded to the AI application. The AI scored each WSI as positive or negative for malignancy (i.e., computer‐aided diagnosis [CADx]). For each WSI, the AI prioritized cytologic tiles by the likelihood that malignant material was present in the tile. Via the AI, blinded cytologists reviewed all WSIs and provided interpretations (i.e., computer‐aided detection [CADe]). The diagnostic accuracies of the WSI evaluation via CADx, CADe, and the original clinical cytologic interpretation (official cytologic interpretation [OCI]) were compared. Results Of the 84 WSIs, 15 were positive, 42 were negative, and 27 were indeterminate after central review. The WSIs generated on average 141,950 tiles each. Cytologists using the AI evaluated 10.5 tiles per WSI before making an interpretation. Additionally, cytologists required an average of 84.1 s of total WSI evaluation. WSI interpretation accuracies for CADx (0.754; 95% CI, 0.622–0.859), CADe (0.807; 95% CI, 0.750–0.856), and OCI (0.807; 95% CI, 0.671–0.900) were similar. Conclusions This trial demonstrates that an AI application allows cytologists to perform a triaged review of WSIs while maintaining accuracy.

AbstractCollision tumors, defined as “two independent neoplasms that occur in close proximity to one another but maintain distinct boundaries,” are quite rare. We report an exceptional collision tumor composed of a genetically confirmed malignant glomus tumor and a fumarate hydratase (FH)‐deficient leiomyoma, presenting as a subcutaneous thigh mass in a 38‐year‐old male who was known to have hereditary leiomyomatosis and renal cell carcinoma syndrome. Microscopic examination identified a biphasic subcutaneous mass comprising sheets and nodules of glomus cells, with nuclear atypia and mitotic activity, and fascicles of mitotically inactive smooth muscle with variably pleomorphic nuclei and intracytoplasmic eosinophilic inclusions, features of FH‐deficient leiomyoma. Immunohistochemistry demonstrated loss of FH and robust 2‐succinocysteine expression in the smooth muscle, with a normal (FH‐retained) expression pattern in the glomus tumor. Next‐generation sequencing, performed on the glomus tumor component, identified CARMN::NOTCH2 fusion, characteristic of malignant glomus tumors. Awareness of the distinctive morphologic, immunohistochemical, and molecular genetic features of glomus tumors and FH‐deficient leiomyomas is important for correct clinical management of patients with exceptional collision tumors of this type.

Myxofibrosarcomas (MFS) present as slowly enlarging superficial masses in elderly patients. Even though these tumors fail to exhibit a distinct immunophenotype, diagnosis is straightforward when they present in subcutaneous tissue. Intramuscular MFS, however, are more challenging to diagnose as the differential also includes dedifferentiated liposarcoma with myxoid features. The vast majority of dedifferentiated liposarcomas show MDM2 amplification, whereas limited data exists as to the MDM2 status of MFS. We sought to explore the rate of MDM2 amplification in cases of classic MFS. Our archives were searched for MFS; only subcutaneous well-sampled resections were included. FISH for MDM2 amplification was performed on each tumor. A cohort of myxoid dedifferentiated liposarcoma resections was studied for comparison. Twenty-two MFS arose in patients aged 44 to 85 years. All tumors contained an infiltrative population of atypical cells embedded in a myxoid stroma with curvilinear blood vessels. MDM2 amplification by FISH was identified in 3 (of 22; 14%) tumors. Available follow up on 17 patients (range 1-96 months; median 13 months) revealed 6 patients with local recurrence and 1 with distant metastasis. Of 3 patients with MDM2- amplified MFS, 1 experienced recurrence and died of unrelated causes, while the second was alive without disease 12 months after diagnosis. Even though the rate of MDM2 amplification by FISH in MFS appears to be low, a subset of cases may show this genetic alteration, which pathologists should be aware of to avoid misclassification as myxoid dedifferentiated liposarcomas. Further studies are necessary to determine if amplification status adds prognostic value.